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1.
Shugo Suzuki Karen L. Pennington Hua Naranmandura Samuel M. Cohen 《Toxicology and applied pharmacology》2010,244(2):99-105
Based on epidemiological data, chronic exposure to high levels of inorganic arsenic in drinking water is carcinogenic to humans, inducing skin, urinary bladder and lung tumors. In vivo, inorganic arsenic is metabolized to organic methylated arsenicals including the highly toxic dimethylarsinous acid (DMAIII) and monomethylarsonous acid (MMAIII). Short-term treatment of rats with 100 μg/g trivalent arsenic (AsIII) as sodium arsenite in the diet or in drinking water induced cytotoxicity and necrosis of the urothelial superficial layer, with increased cell proliferation and hyperplasia. The objectives of this study were to determine if these arsenic-induced urothelial effects are dose responsive, the dose of arsenic at which urothelial effects are not detected, and the urinary concentrations of the arsenical metabolites. We treated female F344 rats for 5 weeks with sodium arsenite at dietary doses of 0, 1, 10, 25, 50, and 100 ppm. Cytotoxicity, cell proliferation and hyperplasia of urothelial superficial cells were increased in a dose-responsive manner, with maximum effects found at 50 ppm AsIII. There were no effects at 1 ppm AsIII. The main urinary arsenical in AsIII-treated rats was the organic arsenical dimethylarsinic acid (DMAV). The thio-metabolites dimethylmonothioarsinic acid (DMMTAV) and monomethylmonothioarsinic acid (MMMTAV) were also found in the urine of AsIII-treated rats. The LC50 concentrations of DMMTAV for rat and human urothelial cells in vitro were similar to trivalent oxygen-containing arsenicals. These data suggest that dietary AsIII-induced urothelial cytotoxicity and proliferation are dose responsive, and the urothelial effects have a threshold corresponding to the urinary excretion of measurable reactive metabolites. 相似文献
2.
Samuel M. Cohen Lora L. Arnold Michal Eldan Ari S. Lewis Barbara D. Beck 《Critical reviews in toxicology》2013,43(2):99-133
Monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV) are active ingredients in pesticidal products used mainly for weed control. MMAV and DMAV are also metabolites of inorganic arsenic, formed intracellularly, primarily in liver cells in a metabolic process of repeated reductions and oxidative methylations. Inorganic arsenic is a known human carcinogen, inducing tumors of the skin, urinary bladder, and lung. However, a good animal model has not yet been found. Although the metabolic process of inorganic arsenic appears to enhance the excretion of arsenic from the body, it also involves formation of methylated compounds of trivalent arsenic as intermediates. Trivalent arsenicals (whether inorganic or organic) are highly reactive compounds that can cause cytotoxicity and indirect genotoxicity in vitro. DMAV was found to be a bladder carcinogen only in rats and only when administered in the diet or drinking water at high doses. It was negative in a two-year bioassay in mice. MMAV was negative in 2-year bioassays in rats and mice. The mode of action for DMAV-induced bladder cancer in rats appears to not involve DNA reactivity, but rather involves cytotoxicity with consequent regenerative proliferation, ultimately leading to the formation of carcinoma. This critical review responds to the question of whether DMAV-induced bladder cancer in rats can be extrapolated to humans, based on detailed comparisons between inorganic and organic arsenicals, including their metabolism and disposition in various animal species. The further metabolism and disposition of MMAV and DMAV formed endogenously during the metabolism of inorganic arsenic is different from the metabolism and disposition of MMAV and DMAV from exogenous exposure. The trivalent arsenicals that are cytotoxic and indirectly genotoxic in vitro are hardly formed in an organism exposed to MMAV or DMAV because of poor cellular uptake and limited metabolism of the ingested compounds. Furthermore, the evidence strongly supports a nonlinear dose-response relationship for the biologic processes involved in the carcinogenicity of arsenicals. Based on an overall review of the evidence, using a margin-of-exposure approach for MMAV and DMAV risk assessment is appropriate. At anticipated environmental exposures to MMAV and DMAV, there is not likely to be a carcinogenic risk to humans. 相似文献
3.
Vichaya Charoensuk Wendy P. Gati Michael Weinfeld X. Chris Le 《Toxicology and applied pharmacology》2009,239(1):64-70
Arsenic trioxide, As2O3, has successfully been used to treat acute promyelocytic leukemia (APL). Induction of apoptosis in cancerous cells has been proposed to be the underlying mechanism for the therapeutic efficacy of arsenic. To further understand the cytotoxicity of arsenic compounds in APL cells, HL-60 cells were exposed to graded concentrations of the following arsenicals for up to 48 h: arsenic trioxide (AsIII), sodium arsenate (AsV), phenylarsine oxide (PAOIII), monomethylarsonous acid (MMAIII), monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV), and the viability and modes of cell death assessed. The arsenic-exposed cells were stained with annexin V-PE and 7-aminoactinomycin D (7-AAD) and analyzed by flow cytometry in order to detect apoptotic and viable cells while cell morphology was visualized using scanning and transmission electron microscopy. Acridine orange staining and microtubule-associated protein 1 light chain 3 (MAP-LC3) detection were used to recognize autophagic cell death. The results showed that the compounds reduced viable HL-60 cells by inducing apoptosis in a concentration-dependent manner. None of the compounds tested caused a significant change in binding of acridine orange or redistribution of MAP-LC3. Potencies of the six different arsenic compounds tested were ranked as PAOIII > MMAIII ≥ AsIII > AsV > MMAV > DMAV. An increase in caspase-3 activity by PAOIII, MMAIII and DMAV implied that these compounds induced apoptosis in HL-60 cells through a caspase-dependent mechanism, but the other arsenic compounds failed to activate caspase-3, suggesting that they induce apoptosis by an alternative pathway. 相似文献
4.
Katharina Krüger Heidrun Straub Jörg Hippler Ulrich Muβhoff 《Toxicology and applied pharmacology》2009,236(1):115-123
Arsenite and its metabolites, dimethylarsinic or dimethylarsinous acid, have previously been shown to disturb synaptic transmission in hippocampal slices of rats (Krüger, K., Gruner, J., Madeja, M., Hartmann, L.M., Hirner, A.V., Binding, N., Muβhoff, U., 2006a. Blockade and enhancement of glutamate receptor responses in Xenopus oocytes by methylated arsenicals. Arch. Toxicol. 80, 492-501, Krüger, K., Straub, H., Binding, N., Muβhoff, U., 2006b. Effects of arsenite on long-term potentiation in hippocampal slices from adult and young rats. Toxicol. Lett. 165, 167-173, Krüger, K., Repges, H., Hippler, J., Hartmann, L.M., Hirner, A.V., Straub, H., Binding, N., Muβhoff, U., 2007. Effects of dimethylarsinic and dimethylarsinous acid on evoked synaptic potentials in hippocampal slices of young and adult rats. Toxicol. Appl. Pharmacol. 225, 40-46). The present experiments investigate, whether the important arsenic metabolites monomethylarsonic acid (MMAV) and monomethylarsonous acid (MMAIII) also influence the synaptic functions of the hippocampus.In hippocampal slices of young (14-21 days-old) and adult (2-4 months-old) rats, evoked synaptic field potentials from the Schaffer collateral-CA1 synapse were measured under control conditions and during and after 30 and 60 min of application of the arsenic compounds.MMAV had no effect on the synapse functions neither in slices of adult nor in those from young rats. However, MMAIII strongly influenced the synaptic transmission: it totally depressed the amplitudes of fEPSPs at concentrations of 50 μmol/l (adult rats) and 25 μmol/l (young rats) and LTP amplitudes at concentrations of 25 μmol/l (adult rats) and 10 μmol/l (young rats), respectively. In contrast, application of 1 μmol/l MMAIII led to an enhancement of the LTP amplitude in young rats, which is interpretable by an enhancing effect on NMDA receptors and a lack of the blocking effect on AMPA receptors at this concentration (Krüger, K., Gruner, J., Madeja, M., Hartmann, L.M., Hirner, A.V., Binding, N., Muβhoff, U., 2006a. Blockade and enhancement of glutamate receptor responses in Xenopus oocytes by methylated arsenicals. Arch. Toxicol. 80, 492-501).These effects are probably not mediated by changes in cell excitability or in presynaptic glutamate release rates, since antidromically induced population spikes and paired-pulse facilitation failed to show any MMAIII effect. The impairment of the excitatory CA1 synapse is more likely caused by the action of MMAIII on postsynaptic glutamatergic receptors and may be jointly responsible for dysfunctions of cognitive effects in arsenic toxicity. 相似文献
5.
6.
A new metabolic pathway of arsenite: arsenic–glutathione complexes are substrates for human arsenic methyltransferase Cyt19 总被引:3,自引:0,他引:3
The metabolism of arsenic is generally accepted to proceed by repetitive reduction and oxidative methylation; the latter is mediated by arsenic methyltransferase (Cyt19). In human urine, the major metabolites of inorganic arsenicals such as arsenite (iAsIII) and arsenate (iAsV) are monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV). On the other hand, in rat bile, the major metabolites of iAsIII have been reported to be arsenic–glutathione (As-GSH) complexes. In the present study we investigate whether these As-GSH complexes are substrates for arsenic methyltransferase by using human recombinant Cyt19. Analyses by high-performance liquid chromatography–inductively coupled plasma mass spectrometry suggested that arsenic triglutathione (ATG) was generated nonenzymatically from iAsIII when GSH was present at concentrations 2 mM or higher. Human recombinant Cyt19 catalyzed transfer of a methyl group from S-adenosyl-l-methionine to arsenic and produced monomethyl and dimethyl arsenicals. The methylation of arsenic was catalyzed by Cyt19 only when ATG was present in the reaction mixture. Moreover, monomethylarsonic diglutathione (MADG) was a substrate of Cyt19 for further methylation to dimethylarsinic glutathione (DMAG). On the other hand, monomethylarsonous acid (MMAIII), a hydrolysis product of MADG, was not methylated to dimethyl arsenical by Cyt19. These results suggest that As-GSH complexes such as ATG and MADG were converted by Cyt19 to MADG and DMAG, respectively. Both MADG and DMAG were unstable in solution when the GSH concentration was lower than 1 mM, and were hydrolyzed and oxidized to MMAV and DMAV, respectively. Metabolism of iAsIII to methylated arsenicals by Cyt19 was via ATG and MADG rather than by oxidative methylation of iAsIII and MMAIII. 相似文献
7.
Metabolism of arsenic and its toxicological relevance 总被引:1,自引:0,他引:1
Arsenic is a worldwide environmental pollutant and a human carcinogen. It is well recognized that the toxicity of arsenicals largely depends on the oxidoreduction states (trivalent or pentavalent) and methylation levels (monomethyl, dimethyl, and trimethyl) that are present during the process of metabolism in mammals. However, presently, the specifics of the metabolic pathway of inorganic arsenicals have yet to be confirmed. In mammals, there are two possible mechanisms that have been proposed for the metabolic pathway of inorganic arsenicals, oxidative methylation, and glutathione conjugation. Oxidative methylation, which was originally proposed in fungi, is based on findings that arsenite (iAsIII) is sequentially converted to monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV) in both humans and in laboratory animals such as mice and rats. However, recent in vitro observations have demonstrated that arsenic is only methylated in the presence of glutathione (GSH) or other thiol compounds, which strongly suggests that arsenic is methylated in trivalent forms. The glutathione conjugation mechanism is supported by findings that have shown that most intracellular arsenicals are trivalent and excreted from cells as GSH conjugates. Since non-conjugated trivalent arsenicals are highly reactive with thiol compounds and are easily converted to less toxic corresponding pentavalent arsenicals, the arsenic–glutathione conjugate stability may be the most important factor for determining the toxicity of arsenicals. In addition, “being a non-anionic form” also appears to be a determinant of the toxicity of oxo-arsenicals or thioarsenicals. The present review discusses both the metabolism of arsenic and the toxicity of arsenic metabolites. 相似文献
8.
Hamdi M Yoshinaga M Packianathan C Qin J Hallauer J McDermott JR Yang HC Tsai KJ Liu Z 《Toxicology and applied pharmacology》2012,262(2):185-193
Arsenic methylation is an important cellular metabolic process that modulates arsenic toxicity and carcinogenicity. Biomethylation of arsenic produces a series of mono-, di- and tri-methylated arsenic metabolites that can be detected in tissues and excretions. Here we report that zebrafish exposed to arsenite (AsIII) produces organic arsenicals, including MMAIII, MMAV and DMAV with characteristic tissue ratios, demonstrating that an arsenic methylation pathway exists in zebrafish. In mammals, cellular inorganic arsenic is methylated by a SAM-dependent arsenic methyltransferase, AS3MT. A zebrafish arsenic methyltransferase homolog, As3mt, was identified by sequence alignment. Western blotting analysis showed that As3mt was universally expressed in zebrafish tissues. Prominent expression in liver and intestine correlated with methylated arsenic metabolites detected in those tissues. As3mt was expressed in and purified from Escherichia coli for in vitro functional studies. Our results demonstrated that As3mt methylated AsIII to DMAV as an end product and produced MMAIII and MMAV as intermediates. The activity of As3mt was inhibited by elevated concentrations of the substrate AsIII as well as the metalloid selenite, which is a well-known antagonistic micronutrient of arsenic toxicity. The activity As3mt was abolished by substitution of either Cys160 or Cys210, which corresponds to conserved cysteine residues in AS3MT homologs, suggesting that they are involved in catalysis. Expression in zebrafish of an enzyme that has a similar function to human and rodent orthologs in catalyzing intracellular arsenic biomethylation validates the applicability of zebrafish as a valuable vertebrate model for understanding arsenic-associated diseases in humans. 相似文献
9.
Trivalent methylated arsenical-induced phosphatidylserine exposure and apoptosis in platelets may lead to increased thrombus formation 总被引:1,自引:0,他引:1
Trivalent methylated metabolites of arsenic, monomethylarsonous acid (MMAIII) and dimethylarsinous acid (DMAIII), have been found highly reactive and toxic in various cells and in vivo animal models, suggesting their roles in the arsenic-associated toxicity. However, their effects on cardiovascular system including blood cells, one of the most important targets for arsenic toxicity, remain poorly understood. Here we found that MMAIII and DMAIII could induce procoagulant activity and apoptosis in platelets, which play key roles in the development of various cardiovascular diseases (CVDs) through excessive thrombus formation. In freshly isolated human platelets, treatment of MMAIII resulted in phosphatidylserine (PS) exposure, a hallmark of procoagulant activation, accompanied by distinctive apoptotic features including mitochondrial membrane potential disruption, cytochrome c release, and caspase-3 activation. These procoagulant activation and apoptotic features were found to be mediated by the depletion of protein thiol and intracellular ATP, and flippase inhibition by MMAIII, while the intracellular calcium increase or reactive oxygen species generation was not involved. Importantly, increased platelet procoagulant activity by MMAIII resulted in enhanced blood coagulation and excessive thrombus formation in a rat in vivo venous thrombosis model. DMAIII also induced PS-exposure with apoptotic features mediated by protein thiol depletion, which resulted in enhanced thrombin generation. In summary, we believe that this study provides an important evidence for the role of trivalent methylated arsenic metabolites in arsenic-associated CVDs, giving a novel insight into the role of platelet apoptosis in toxicant-induced cardiovascular toxicity. 相似文献
10.
Csaba Pankucsi Tamás Bányász János Magyar Ildikó Gyönös Anikó Kovács András Varró Gábor Szénási Péter P. Nánási 《Naunyn-Schmiedeberg's archives of pharmacology》1997,355(3):398-405
The cellular electrophysiological effects of EGIS-7229 (5-chlor-4-[N-(3,4-dimethoxy-phenyl-ethyl)-amino-propylamino]-3(2H)-pyridazinone
fumarate), a novel antiarrhythmic agent, was studied using conventional microelectrode techniques in canine cardiac Purkinje
fibers and papillary muscle preparations obtained from man, rabbits and guinea pigs. Low concentration of EGIS-7229 (3 μmol/l)
selectively lengthened action potential duration (both APD50 and APD90) in all preparations. The effect of higher concentrations (30–100 μmol/l) of EGIS-7229 on action potential duration was variable
depending on the preparation studied: in rabbit and human papillary muscles both APD50 and APD90 were lengthened, in canine Purkinje fibers APD90 was lengthened but APD50 was shortened, while in guinea pig papillary muscles both APD50 and APD90 were shortened by high concentrations of the drug. At these higher concentrations EGIS-7229 also decreased the maximum velocity
of action potential upstroke (V
max) and depressed the plateau of action potentials without affecting the resting membrane potential or action potential amplitude.
Both reduction of V
max and lengthening of APD were frequency dependent. The former effect was more prominent at higher pacing frequencies, while
the latter was more pronounced at lower driving rates. In guinea pig papillary muscle, the time constant of recovery from
V
max-block was 719 ± 33 ms (n = 18) and the rate of onset of the block was 1.81 ± 0.06 AP–1 (n = 16) in the presence of 100 μmol/l EGIS-7229. EGIS-7229 had a complex action on refractoriness in guinea pig papillary muscles:
ERP was lengthened at low concentrations (3 to 10 μmol/l), unchanged at 30 μmol/l and shortened at 100 μmol/l. The ratio of
ERP/APD90, however, was significantly increased at concentrations higher than 3 μmol/l.
In canine Purkinje fiber, when the delayed rectifier K current (IK) was blocked by d-sotalol (60 μmol/l) and APD was shortened back to its control value by additional application of nicorandil
(15 μmol/l), APD was not affected by 3 μmol/l but was shortened by 30 μmol/l of EGIS-7229. 100 μmol/l EGIS-7229 shortened
APD in guinea pig papillary muscle. This effect of EGIS-7229 was effectively prevented by nifedipine pretreatment (10 μmol/l).
In this preparation, EGIS-7229 also decreased the V
max of the slow action potential, evoked in the presence of 20 mmol/l external K+ plus 0.5 mmol/l Ba2+.
It is likely that EGIS-7229 at low concentrations blocks IK in human, canine, rabbit and guinea pig cardiac preparations, but at higher concentrations also inhibits Ca and Na currents.
Therefore, EGIS-7229 appears to carry mixed class III, IV and IB antiarrhythmic properties.
Received: 8 July 1996 / Accepted: 23 October 1996 相似文献
11.
Shugo Suzuki Lora L. Arnold Karen L. Pennington Baowei Chen X. Chris Le Samuel M. Cohen 《Toxicology letters》2009
Arsenite (AsIII), an inorganic arsenical, is a known human carcinogen, inducing tumors of the skin, urinary bladder and lung. It is known to be metabolized to organic methylated arsenicals in vivo. AsIII has been reported to have the ability to up-regulate the epidermal growth factor receptor (EGFR)-associated pathway in epithelial cells, including human urothelial cells in vitro. EGFR is a cell-surface receptor belonging to the ErbB family of receptor tyrosine kinases, and the EGFR-associated signaling pathway has been reported to play an important role in carcinogenesis and cancer progression, including in bladder cancer. In this study, we investigated the growth effects of AsIII and an organic trivalent arsenical, dimethylarsinous acid (DMAIII), and the effects of co-exposure of gefitinib, an EGFR inhibitor, with AsIII to a rat urothelial cell line (MYP3). We also investigated the effects of co-administration of dietary AsIII and gefitinib in vivo. In vitro, concentrations of 1.0 μM AsIII or 0.5 μM DMAIII induced cytotoxicity. However, lower concentrations of AsIII treatment had a slight mitogenic growth effect whereas lower concentrations of DMAIII did not. Gefitinib blocked AsIII-induced cell growth in vitro. In vivo, a high dose of gefitinib alone induced slight urothelial cytotoxicity, and did not reduce cytotoxicity and regenerative cell proliferation when co-administered with AsIII. The majority of arsenic metabolites present in the urine of AsIII-treated rats were organic arsenicals, mainly dimethylarsinic acid (DMAV). AsIII was also present, and its concentration was higher than the concentration required to produce cytotoxicity in vitro. These data suggest that an EGFR inhibitor has the ability to block AsIII-induced cell proliferation in vitro but not in vivo in a short-term study. 相似文献
12.
K Rehman Z Chen WW Wang YW Wang A Sakamoto YF Zhang H Naranmandura N Suzuki 《Toxicology and applied pharmacology》2012,263(3):273-280
Arsenic binding to biomolecules is considered one of the major toxic mechanisms, which may also be related to the carcinogenic risks of arsenic in humans. At the same time, arsenic is also known to activate the phosphorylation-dependent signaling pathways including the epidermal growth factor receptor, the mitogen-activated protein kinase and insulin/insulin-like growth factor-1 pathways. These signaling pathways originate at the level of receptor tyrosine kinases whose phosphorylation status is regulated by opposing protein tyrosine phosphatase (PTP) activity. Reversible tyrosine phosphorylation, which is governed by the balanced action of protein tyrosine kinases and phosphatases, regulates important signaling pathways that are involved in the control of cell proliferation, adhesion and migration. In the present study, we have focused on the interaction of cellular PTPs with toxic trivalent arsenite (iAsIII) and its intermediate metabolites such as monomethylarsonous acid (MMAIII) and dimethylarsinous acid (DMAIII) in vitro, and then determined the arsenic binding site in PTP by the use of recombinant PTPs (e.g., PTP1B and CD45). Interestingly, the activities of PTP1B (cytoplasm-form) or CD45 (receptor-linked form) were observed to be strongly inhibited by both methylated metabolites (i.e., MMAIII and DMAIII) but not by iAsIII. Matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS) has clearly confirmed that the organic intermediate, DMAIII directly bound to the active site cysteine residue of PTP1B (e.g., Cys215), resulting in inhibition of enzyme activity. These results suggest that arsenic exposure may disturb the cellular signaling pathways through PTP inactivation. 相似文献
13.
Hua Naranmandura Katsuya Iwata Yasumitsu Ogra 《Toxicology and applied pharmacology》2010,245(1):67-75
Arsenic toxicity and distribution are highly dependent on animal species and its chemical species. Recently, thioarsenical has been recognized in highly toxic arsenic metabolites, which was commonly found in human and animal urine. In the present study, we revealed the mechanism underlying the distribution and metabolism of non-thiolated and thiolated dimethylarsenic compounds such as dimethylarsinic acid (DMAV), dimethylarsinous acid (DMAIII), dimethylmonothioarsinic acid (DMMTAV), and dimethyldithioarsinic acid (DMDTAV) after the administration of them into femoral vein of hamsters. DMAV and DMDTAV distributed in organs and body fluids were in their unmodified form, while DMAIII and DMMTAV were bound to proteins and transformed to DMAV in organs. On the other hand, DMAV and DMDTAV were mostly excreted into urine as their intact form 1 h after post-injection, and more than 70% of the doses were recovered in urine as their intact form. By contrast, less than 8-14% of doses were recovered in urine as DMAV, while more than 60% of doses were distributed in muscles and target organs (liver, kidney, and lung) of hamsters after the injection of DMMTAV and DMAIII. However, in red blood cells (RBCs), only a small amount of the arsenicals was distributed (less than 4% of the doses) after the injection of DMAIII and DMMTAV, suggesting that the DMAIII and DMMTAV were hardly accumulated in hamster RBCs. Based on these observations, we suggest that although DMMTAV and DMDTAV are thioarsenicals, DMMTAV is taken up efficiently by organs, in a manner different from that of DMDTAV. In addition, the distribution and metabolism of DMMTAV are like in manner similar to DMAIII in hamsters, while DMDTAV is in a manner similar to DMAV. 相似文献
14.
The actions were examined of 17 frequently used glycol ether compounds on the glutamate receptor-mediated ion currents. The
receptors were expressed in Xenopus oocytes by injection of rat brain mRNA. Most of the 17 glycol ethers exerted no effects on the glutamate subreceptors activated
by kainate and N-methyl-d-aspartate (NMDA), whereas 2-phenoxyethanol (ethylene glycol monophenyl ether) caused a considerable reduction of NMDA-induced
membrane currents in a reversible and concentration-dependent manner. The threshold concentration of the ethylene glycol monophenyl
ether effect was <10 μmol/l. The concentration for a 50% inhibition (IC50) was ∼360 μmol/l. The results indicate a neurotoxic potential for 2-phenoxyethanol.
Received: 13 October 1998 / Accepted: 24 November 1998 相似文献
15.
Shi Xu Yan Fang Zhang Micheal W. Carew Wen Hui Hao Jacky Fong Chuen Loo Hua Naranmandura X. Chris Le 《Archives of toxicology》2013,87(6):1013-1023
Arsenic trioxide (As2O3) is established as one of the most effective drugs for treatment of patients with acute promyelocytic leukemia, as well as other types of malignant tumors. However, HL-60 cells are resistant to As2O3, and little is known about the underlying resistance mechanism for As2O3 and its biomethylation products, namely, monomethylarsonous acid (MMAIII) on the treatment of tumors. In the present study, we investigated the molecular mechanisms underlying iAsIII and its intermediate metabolite MMAIII-induced anticancer effects in the HL-60 cells. Here, we show that the HL-60 cells exhibit resistance to inorganic iAsIII (IC50 = 10 μM), but are relatively sensitive to its intermediate MMAIII (IC50 = 3.5 μM). Moreover, we found that the multidrug resistance protein 1 (MRP1), but not MRP2, is expressed in HL-60 cells, which reduced the intracellular arsenic accumulation, and conferred resistance to inorganic iAsIII and MMAIII. Pretreatment of HL-60 with MK571, an inhibitor of MRP1, significantly increased iAsIII and MMAIII-induced cytotoxicity and arsenic accumulations, suggesting that the expression of MRP1/4 may lead to HL-60 cells resistance to trivalent arsenic compounds. 相似文献
16.
Monomethylarsonous acid (MMAIII), a trivalent metabolite of arsenic, is highly cytotoxic and recent cell culture studies suggest that it might act as a carcinogen. The general consensus of studies indicates that the cytotoxicity of MMAIII is a result of increased levels of reactive oxygen species (ROS). A longstanding relationship between arsenic and selenium metabolism has led to the use of selenium as a supplement in arsenic exposed populations, however the impact of organic arsenicals (methylated metabolites) on selenium metabolism is still poorly understood. In this study we determined the impact of exposure to MMAIII on the regulation of expression of TrxR1 and its activity using a primary lung fibroblast line, WI-38. The promoter region of the gene encoding the selenoprotein thioredoxin reductase 1 (TrxR1) contains an antioxidant responsive element (ARE) that has been shown to be activated in the presence of electrophilic compounds. Results from radiolabeled selenoproteins indicate that exposure to low concentrations of MMAIII resulted in increased synthesis of TrxR1 in WI-38 cells, and lower incorporation of selenium into other selenoproteins. MMAIII treatment led to increased mRNA encoding TrxR1 in WI-38 cells, while lower levels of mRNA coding for cellular glutathione peroxidase (cGpx) were detected in exposed cells. Luciferase activity of TrxR1 promoter fusions increased with addition of MMAIII, as did expression of a rat quinone reductase (QR) promoter fusion construct. However, MMAIII induction of the TRX1 promoter fusion was abrogated when the ARE was mutated, suggesting that this regulation is mediated via the ARE. These results indicate that MMAIII alters the expression of selenoproteins based on a selective induction of TrxR1, and this response to exposure to organic arsenicals that requires the ARE element. 相似文献
17.
Klinger F Geier P Dorostkar MM Chandaka GK Yousuf A Salzer I Kubista H Boehm S 《British journal of pharmacology》2012,166(5):1631-1642
BACKGROUND AND PURPOSE
Flupirtine is a non-opioid analgesic that has been in clinical use for more than 20 years. It is characterized as a selective neuronal potassium channel opener (SNEPCO). Nevertheless, its mechanisms of action remain controversial and are the purpose of this study.EXPERIMENTAL APPROACH
Effects of flupirtine on native and recombinant voltage- and ligand-gated ion channels were explored in patch-clamp experiments using the following experimental systems: recombinant KIR3 and KV7 channels and α3β4 nicotinic acetylcholine receptors expressed in tsA 201 cells; native voltage-gated Na+, Ca2+, inward rectifier K+, KV7 K+, and TRPV1 channels, as well as GABAA, glycine, and ionotropic glutamate receptors expressed in rat dorsal root ganglion, dorsal horn and hippocampal neurons.KEY RESULTS
Therapeutic flupirtine concentrations (≤10 µM) did not affect voltage-gated Na+ or Ca2+ channels, inward rectifier K+ channels, nicotinic acetylcholine receptors, glycine or ionotropic glutamate receptors. Flupirtine shifted the gating of KV7 K+ channels to more negative potentials and the gating of GABAA receptors to lower GABA concentrations. These latter effects were more pronounced in dorsal root ganglion and dorsal horn neurons than in hippocampal neurons. In dorsal root ganglion and dorsal horn neurons, the facilitatory effect of therapeutic flupirtine concentrations on KV7 channels and GABAA receptors was comparable, whereas in hippocampal neurons the effects on KV7 channels were more pronounced.CONCLUSIONS AND IMPLICATIONS
These results indicate that flupirtine exerts its analgesic action by acting on both GABAA receptors and KV7 channels. 相似文献18.
Thioarsenicals have been paid much attention due to the toxicity of arsenic, since some of them are highly toxic and commonly found in the urine of mammals. We previously reported that thioarsenicals might be produced in red blood cells (RBCs). Here, we further characterized the mechanism underlying the production and metabolism of thioarsenicals in RBCs using 34S-labeled dimethylmonothioarsinic acid (34S-DMMTAV) and purified rat hemoglobin (Hb) or a rat RBC lysate. 34S-DMMTAV did not bind to Hb on incubation with purified rat Hb, remaining in its original form. However, when 34S-DMMTAV was incubated with a rat RBC lysate, only arsenic, i.e., not sulfur (34S), was detected in a form bound to Hb (As-Hb). In addition, another arsenic product containing sulfur (34S) in the molar ratio of 34S/As = 2 was detected, which was assigned as dimethyldithioarsinic acid (DMDTAV), suggesting that arsenic does not bind to Hb in the form of 34S-DMMTAV but does so in the form of dimethylarsinous acid (DMAIII). Namely, DMMTAV appeared to be hydrolyzed into dimethylarsinic acid (DMAV) and H34S-, and the released H34S- reacted with DMMTAV to produce DMDTAV. Thus, DMMTAV was transformed into DMDTAV and DMAV (2DMMTAV - > DMDTAV + DMAV), the latter product being reduced to DMAIII in the presence of GSH and bound to Hb. In a separate experiment, 34S-DMMTAV was incubated with sulfide (Na2S) and GSH. Although DMMTAV was not transformed into DMDTAV in the presence of only Na2S or GSH, it was transformed into DMDTAV in the presence of both Na2S and GSH. Our results suggest that DMMTAV is hydrolyzed enzymatically into DMAV and sulfide, the former being reduced to DMAIII and bound to Hb, and the latter reacting with DMMTAV to yield DMDTAV. Thus, DMMTAV is transformed into DMDTAV and DMAV through a hydrolytic reaction in a manner similar to a disproportionation reaction, DMAV being reduced and bound to Hb (As-Hb), and DMDTAV being produced more in the presence of sulfides in the medium. 相似文献
19.
Tetsu Matsubara Craig Clarkson Luc Hondeghem 《Naunyn-Schmiedeberg's archives of pharmacology》1987,336(2):224-231
Summary Guinea-pig papillary muscles were voltage-clamped using the single sucrose gap technique. The maximum upstroke velocity of the action potential (V
max) was used as an indicator of the sodium conductance. Lidocaine (5 mol/l to 40 mol/l) reduced V
max in a use-dependent fashion. Block of sodium channels developed during channel opening and while the channels were in-activated. Block of inactivated channels was not voltage-dependent over the –40 mV to +40 mV range. Recovery from block occurs upon repolarization, and for a given diastolic interval the recovery is more complete as the membrane potential is hyperpolarized over the –80 mV to –150 mV range. These results can be accounted for in terms of the modulated receptor hypothesis, where lidocaine has a low affinity for rested sodium channels, but a high affinity for open and inactivated channels.L. Hondeghem is an Established Investigator of the American Heart Association 相似文献
20.
Autoreceptors can modulate 5-hydroxytryptamine release from porcine and human small intestine in vitro 总被引:4,自引:1,他引:4
The effects of 5-hydroxytryptamine (5-HT) receptor agonists and antagonists were studied on the release of 5-HT from enterochromaffin
cells of incubated strips of porcine and human small intestine. Tetrodotoxin (1 μmol/l) was present in the incubation medium
to block neuronally mediated inputs to the enterochromaffin cells. The 5-HT1A receptor agonist (+)-8-hydroxy-dipropylaminotetralin (8-OH-DPAT, 1 μmol/l) and the 5-HT2 receptor agonist α-methyl-5-HT (1 μmol/l) increased 5-HT release by 40% in about 60% of the human preparations.These agonists
showed no effect on 5-HT release in porcine intestinal mucosa. The 5-HT3 receptor agonist 2-methyl-5-HT (3–100 μmol/l) increased 5-HT release in both species by 60% (pig) and 90% (man), respectively.
These stimulatory effects were antagonized by tropisetron (10 nmol/l). The 5-HT4 receptor agonist 5-methoxytryptamine (0.3–30 μmol/l) reduced 5-HT release by about 50% in both species. These inhibitory
effects were antagonized by tropisetron (3 μmol/l). The basal outflow of 5-HT from the intestinal mucosa was not significantly
affected by tropisetron (10 nmol/l; 3 μmol/l). The specific 5-HT4 receptor antagonist GR 113808 ((1-[2-methylsulphonyl)amino]ethyl]-4-piperidinyl]methyl-1-methyl-1H-indole-3-carboxylate)
(0.1 μmol/l) which by itself did not significantly affect 5-HT release from human duodenal specimens blocked the inhibitory
effect of 5-methoxytryptamine (30 μmol/l).
These findings indicate that stimulatory 5-HT3 and inhibitory 5-HT4 receptors are present on enterochromaffin cells of the porcine and human intestinal mucosa. Under the present experimental
conditions endogenous 5-HT does not significantly activate these receptors. Stimulatory 5-HT1A and 5-HT2 receptors may additionally be present on human enterochromaffin cells.
Received: 19 September 1997/ Accepted: 29 January 1998 相似文献